5,6-Dihydroxy indole is well known as playing an important role in the production of the organic pigment melanin. This compound also appears to be involved in the process for the formation of eumelanins from, 3,4-dihydroxyphenylalanine [J. Biol. Chem. 172, 83 (1948); Nature, 276,627 (1978)].
5,6-Dihydroxyindole (DHI) and derivatives thereof have been described and used in dye compositions for dyeing keratinous fibers, and especially human hair. See, for example, U.S. Pat. No. 4,808,190, U.S. Pat. No. 5,704,949, U.S. Pat. No. 3,194,734 and U.S. Pat. No. 2,934,396.
5,6-Diacetoxyindole (DAI) has been obtained by reductive cyclization of 4,5-diacetoxy-2,.beta.-dinitrostyrene with Fe in acetic acid. For the reduction of 2 g of this material to DAI, 10 g of Fe, 40 ml of acetic acid and 50 ml of absolute alcohol were required. In addition, for isolation of DAI from the reaction mixture, several extractions with ether (at least 5 times) and recrystallization were necessary.
Isolation of DHI required additional steps after hydrolysis of DAI. (R. J. Beer, K. Clarke, H. G. Khorana, A. Robertson The Chemistry of the Melanins. Part I, The Synthesis of 5,6-Dihydroxyindole and related compounds. J. Chem. Soc., 1948, 2223)
5,6-Dibenzyloxyindole (DBI) has been produced by reductive cyclization of 4,5-dibenzyloxy-2,.beta.-dinitrostyrene with Fe in acetic acid as in Beer et al, supra. 4-5-dibenzyloxy-2,.beta.-dinitrostyrene was made by nitration of 3,4-benzyloxy-.beta.-nitrostyrene.
DHI has been obtained from DBI by hydrogenation in the presence of Pd/C. (J. D. Benigni, R. L. Minnis: The synthesis of 5,6-dihydroxyindole and some of its derivatives, J. Heterocycl, Compd., 1965, 2, 387).
The disadvantages of this synthesis are the same as in Beer et al., supra, since no improvement is made in the reductive cyclization step.
DBI has been obtained by silica gel assisted reductive cyclization of 4,5-dibenzyloxy-2,.beta.-dinitrostyrene. A minimum of 1.5 g of silica gel per mmole of 4,5-dibenzyloxy-2,.beta.-dinitrostyrene are required. (A. K. Sinhababu and R. T. Borchardt: Silica gel assisted reductive cyclization of alkoxy-2,.beta.-dinitrostyrenes to alkoxyindoles, J. Org. Chem. 1983, 3347). The method is expensive and difficult to perform on a large scale.
DAI has been produced by reductive cyclization of 4,5-dibenzyloxy-2,.beta.-dinitrostyrene with 5% Pt/C in acetic acid followed by acetylation. The whole process required 5 operations and HPLC was used to purify the final compound DAI. (B. P. Murphy, Efficient synthesis of 5,6-diacetoxyindole: A stable eumelanin precursor. J. Org. Chem. 1985, 5873)
DAI has been obtained from 4,5-dihydroxy-2,.beta.-dinitrostyrene by hydrogenation of an aqueous dispersion over 10% Pd/C.
4,5-dihydroxy-2,.beta.-dinitrostyrene was obtained from 4,5-dibenzyloxy-2,.beta.-dinitrostyrene by refluxing with CF.sub.3 CO.sub.2 H for three hours in argon atmosphere: (B. P. Murphy, H. D. Banks, Synthesis of 5,6-dihydroxyindole: A novel reductive cyclization of (E)-4,5-dihydroxy-2,.beta.-dinitrostyrene. Synthetic Commun. 15(4), 1985, 321; B. P. Murphy, T. M. Schultz. Synthesis and physical properties of 5,6-dihydroxyindole. J. Org. Chem. 1985, 50, 2790).
DAI has been obtained from 2-methyl-4,5-dibenzyloxy-nitrobenzene by condensation with N,N-dimethylformamide acetals and reduction with Raney nickel catalyst. This method requires protection of the phenolic groups and somewhat expensive reagents and catalysts (A. D. Batcho, W. Leimgruber, Organic Syntheses Coll. Vol. VII, 1990).
DHI has been produced by hydrogenation of 2-nitro-4,5-dihydroxybenzyl cyanide with Pd/C. Synthesis of 2-nitro-4,5-dihydroxybenzyl cyanide requires 4 steps from 3,4-dimethoxybenzyl cyanide: (DE 3737825 A1 L'Oreal, Paris Fr (May 1988)).
DAI has been obtained from trans-4,5-dibenzyloxy-.beta.-pyrrolidino-2-nitrostyrene by a "one pot" method. Synthesis of trans-4,5-dibenzyloxy-.beta.-pyrrolidino-2-nitrostyrene is performed as described in Batcho et al, supra. (U.S. Pat. No. 5,262,546, (November 1993)).
Known preparative processes do not enable 5,6-disubstituted indoles to be prepared in a satisfactory manner, especially on an industrial scale.
The pivotal step in the synthesis of DHI (or DHI derivatives) is the final reductive cyclization and isolation of the product. Prior art methods require use of precious metal catalysts or high pressure hydrogenation.
It is an object of the present invention to provide a process which is inexpensive, simple to perform (without the need for special equipment) and more easily scaled-up than prior art processes.